An important biosynthetic pathway for the metabolism of arachidonic acid is initiated by the enzyme 5-lipoxygenase (5-LO). The first product formed by the oxidation of arachidonic acid with 5-LO is 5-hydroperoxyeicosatetraenoic acid (5-HPETE) which is subsequently converted to either 5-hydroxyeicosatetraenoic acid (5-HETE) or the leukotriene intermediate LTA.sub.4. Further enzymatic metabolism of LTA.sub.4 leads to the production of LTB.sub.4 and the peptidoleukotrienes (LTC.sub.4, LTD.sub.4, and LTE4).
The above mentioned biosynthetic products of the 5-LO pathway are very potent substances. When present in the nanomolar to picomolar concentration range, these compounds produce a variety of biological effects which are associated with mammalian disease. For example, 5-HETE stimulates tumor growth in epithelial and squamous cell based cancers. The peptidoleukotrienes are known to be potent constrictors of human airway smooth muscle; aerosol administration of these substances to non-asthmatic volunteers has been shown to induce bronchoconstriction. Both LTB.sub.4 and 5-HETE are potent chemotactic factors for inflammatory cells such as polymorphonuclear leukocytes, and both compounds have been isolated in the synovial fluids of arthritic patients.
Disease states in which leukotrienes are important mediators include: adult respiratory distress syndrome, allergic rhinitis, arthritis, asthma, chronic obstructive pulmonary disease, gout, inflammatory bowel disease, ischemic induced myocardial injury, psoriasis, reperfusion injury, spinal cord injury, stroke, and traumatic brain injury.
A chemical compound which acts as an inhibitor of the 5-LO enzyme should be an effective therapeutic agent for the treatment or prevention of these diseases, as well as any other disease which is mediated by products of the 5-LO pathway.